Methylene-4-azasteroids

ABSTRACT

New 17-methylene-4-azasteroid compounds of formula I:  
                 
 
     wherein R 20  and R 20a  each denote fluoro, chloro, bromo or cyano and R 10  and R 4  each denote a hydrogen atom or a methyl group, and R 1  and R 2  each denote a hydrogen atom or together denote an additional bond, are useful for treating diseases or conditions caused by excessive androgen levels, such as acne, prostate diseases, alopecia and hirsutism, as well as gynecological conditions. Methods of synthesizing the new 17-methylene-4-azasteroid compounds are described.

[0001] The present invention comprises novel 17-methylene-4-azasteroidsof general formula I:

[0002] wherein

[0003] R²⁰ and R^(20a), independently of each other, each denote afluoro, chloro, bromo, azido, cyano, isocyano, rhodano, isothiocyano, aC₁-C₄-alkyl or a hydroxy-C₁-C₄-alkyl group,

[0004] R¹⁰ denotes a hydrogen atom or a methyl group,

[0005] R⁴ is selected from the group consisting of hydrogen andC₁-C₄-alkyl groups, and

[0006] R¹ and R² each denote a hydrogen atom or together denote anadditional bond.

[0007] In preferred embodiments of these novel compounds R²⁰ andR^(20a), independently of each other, each denote F, Cl, Br or CN and R⁴is H or Me.

[0008] Methods for preparing novel compounds and for producingpharmaceutical compositions thereof are described.

[0009] The compounds of the invention, 17-methylene-4-azasteroids, arenew; their preparation and their biological activity have thus far notbeen described.

[0010] Preferred compound of formula I include

[0011] E-17-chloromethylene-4-aza-5α-estran-3-one,

[0012] E-17-chloromethylene-4-aza-5α-androstan-3-one,

[0013] E-17-chloromethylene-4-methyl-4-aza-5α-estran-3-one,

[0014] E-17-chloromethylene-4-methyl-4-aza-5α-androstan-3-one,

[0015] E-17-chloromethylene-4-aza-5α-estr-1-en-3-one,

[0016] E-17-chloromethylene-4-aza-5α-androst-1-en-3-one,

[0017] E-17-chloromethylene-4-methyl-4-aza-5α-androst-1-en-3-one,

[0018] E-17-bromomethylene-4-methyl-4-aza-5α-estran-3-one,

[0019] E-17-cyanomethylene-4-methyl-4-aza-5α-estran-3-one,

[0020] Z-17-(1′)-chloroethylidene-4-methyl-4-aza-5α-androstan-3-one,

[0021] Z-17-(1′)-chloroethylidene-4-methyl-4-aza-5α-estran-3-one,

[0022] Z-17-(1′)-bromoethylidene-4-methyl-4-aza-5α-androstan-3-one and

[0023] Z-17-(1′)-bromoethylidene-4-methyl-4-aza-5α-estran-3-one.

[0024] Another object of the present invention are pharmaceuticalcompositions containing as the active ingredient at least one17-methylene-4-azasteroid of general formula I,-and at least one ofappropriate auxiliary agents and carriers.

[0025] The 17-methylene-4-azasteroid compounds of the invention are5α-reductase inhibitors. Hence, they are suitable for the treatment ofdiseases caused by elevated testosterone levels and finallydihydrotestosterone levels in the blood and tissues.

[0026] Diseases induced by excessive androgen effects can also occur atnormal blood testosterone levels if the conversion of testosterone todihydrotestosterone in the tissues is elevated. This is the case, forexample, in idiopathic forms of hirsutism (REF).

[0027] Progesterone plays an important role in the tight closing of theos of uterus (Mahendroo). The softening thereof before giving birth is aresult of local 5α-reductase-induced degradation of progesterone todihydroprogesterone, which is a very weak gestagen. By inhibiting theprogesterone catabolism in this part of the uterus, the substances ofthe invention are therefore also suitable for preventing prematurematuration and opening of the os of uterus.

[0028] 5α-Reduced metabolites of progesterone (REF from Lancet) andother C21-steroids and the metabolites thereof formed in the body, forexample allo-pregnanolone, can act as neurosteroids and can interactwith neurosteroids. Disorders of this function can result in depression.Possible indications for the substances of the invention are prostatediseases, alopecia of the masculine type, acne and hirsutism as well asvarious gynecological clinical conditions such as the premenstrualsyndrome. The appearance of 5α-reduced metabolites of progesterone inthe CNS plays an important role in the onset of such conditions.Premature opening of the os of uterus can be induced by increaseddegradation of progesterone to dihydroprogesterone in this tissue. Thesubstances of the invention are suitable for preventing this catabolismand thus the premature maturation of the cervix uteri. The substances ofthe invention can exert their action by inhibiting the 5α-reduction oftestosterone or progesterone in the organs and tissues affected by thisdisorder. In addition, the blood levels of the 5α-reduced metabolitesare lowered.

[0029] Moreover, the compounds of the invention constitute intermediatesfor the synthesis of other pharmacologically highly active steroidproducts.

[0030] The compounds of the invention are prepared as indicated in theappended method claims.

[0031] According to the invention, the 17-methylene-4-azasteroidcompounds can be derived from the 17-methylene-steroids of generalformula II and general formula VII.

[0032] Compounds according to the invention are obtained by reactingcompounds of general formula II in a known manner with NalO₄ withcatalytic mediation of KMnO₄ in a protic solvent, preferably tert.-BuOH,to form the 3,5-seco keto acid, cyclizing this acid with NH₄OAc inglacial acetic acid to form the unsaturated lactam and then reducingsaid lactam to the saturated lactam of general formula III withHCOOH/K₂CO₃ in DMF:

[0033] further reacting the compounds of general formula III with MeIand NaH in a dipolar aprotic solvent, preferably DMF, to form the4-methyl-substituted compounds of general formula IV:

[0034] and reacting other compounds of general formula III by asilyl-mediated DDQ (2,3-dichloro-5, 6-dicyano-1, 4-benzoquinone)oxidation in a dipolar aprotic solvent, such as dioxane, to form thedehydrogenated lactams of general formula V:

[0035] The compounds of general formula V, like the compounds of generalformula III, are reacted with MeI and NaH to form the4-methyl-substituted lactams of general formula VI:

[0036] Moreover, 17-methylene-4-azasteroid compounds according to theinvention are obtained by subjecting compounds of general formula VII tothe same chemical reactions as the compounds of general formula II, thusforming compounds of general formulas VIII, IX, X and XI.

BRIEF DESCRIPTION OF THE DRAWING

[0037] The objects, features and advantages of the invention will now beillustrated in more detail with the aid of the following description ofthe preferred embodiments, with reference to the accompanying figures inwhich:

[0038]FIG. 1 is a graphical illustration comparing prostate weight incastrated infantile male rats after administration of two examples ofthe 17-methylene-4-azasteroid compounds according to the invention withprostate weight in the rats after administration of CPA and finasteridesto demonstrate the improved antiandrogenic activity of the compoundsaccording to the invention;

[0039]FIG. 2 is a graphical illustration comparing levator ani muscleweight in castrated infantile male rats after administration of17-methylene-4-azasteroid compounds according to the invention with thelevator ani muscle weight in the rats after administration of CPA andfinasterides;

[0040]FIG. 3 is a graphical illustration comparing preputial glandweight in castrated infantile male rats after administration of17-methylene-4-azasteroid compounds according to the invention withpreputial gland weight in the rats after administration of CPA andfinasterides;

[0041]FIG. 4 is a graphical illustration comparing seminal vesicleweight in castrated infantile male rats after administration of17-methylene-4-azasteroid compounds according to the invention withseminal vesicle weight in the rats after administration of CPA andfinasterides; and

[0042]FIG. 5 is a graphical illustration comparing adrenal weight incastrated infantile male rats after administration of17-methylene-4-azasteroid compounds according to the invention with theadrenal weight in the rats after administration of CPA and finasterides.

RESULTS

[0043] Evaluation of antiandrogenic activity of the compounds of theinvention was performed in castrated male rats (see FIGS. 1 to 5/table).Castrated immature male rats were treated for 7 days with testosteronepropionate (TP) and the substances of the invention (0.1 mg of TP aloneand/or 1 mg of 5α-reductase inhibitor/animal/day, s.c., n=5-10/group).The treatment with TP caused a severe increase in weight of theaccessory genital glands (prostate and seminal vesicle). In the animalstreated with the vehicle and with 5α-reductase inhibitor alone, theweights of the examined organs remained at low values. The substances ofthe invention exerted an inhibitory effect in the test systems selected.

[0044] Table I shows that the compounds J 1879 and J 1924 appreciablyreduced the effects of testosterone propionate, TP, on the prostate andseminal vesicle. TABLE I Inhibition of the action of testosteronepropionate (TP) on the growth of the seminal vesicle and prostate. ET01.31: Prostate Seminal vesicle

34 25

39 41

[0045] The studies to determine the IC₅₀ values of the steroids J 1879and J 1924 for the 5α-reductase outside the genital tract were carriedout in four different human bone cell lines (hOB cells). The cells wereincubated for 6 hours with 0.5 μM androstendione (0.1 μM [³H]androstendione; 0.4 μM androstendione) with or without adding increasingconcentrations of the inhibitor (10⁻¹¹-11⁻⁸ M).

[0046] After the incubation, the medium was extracted with chloroform:methanol (2:1, vol:vol), the steroids (substrate and 5α-reducedmetabolites) were separated by thin-layer chromatography, and the DNAcontent of the cells of the samples was determined. The 5α-reductaseactivity (sum of the 5α-reduced metabolites formed: 5α-androstandione,5α-dihydrotestosterone, 5α-androstan-3α, 17β-diol,5α-androstan-3β,17β-diol expressed in pmol/μg DNA/h) was determined induplicate samples. The relative 5α-reductase activity (5α-reductaseactivity of the samples with added inhibitor compared to thecorresponding control values, namely those for the samples without addedinhibitor) is shown in the figure always as a mean±SEM. The IC₅₀ valuesof J1879 and J1924 for the 5α-reductase in bone cells amounted to<10⁻¹⁰M in all cases.

[0047] In addition, within the framework of studies to determine theIC⁵⁰ values of J 1879 and J1924, the inhibiting action of LY 191704, anonsteroidal specific inhibitor of type-1 5α-reductase, finasteride, a4-azasteroid with inhibiting action mainly on type-2 5α-reductase, andprogesterone, a physiological substrate of 5α-reductase, was determinedfor comparative purposes in the four cell lines at a concentration of10⁻⁸ M. It can be seen from the figures that the substances of theinvention inhibited the 5α-reductase in the cell types studied morestrongly and at substantially lower concentrations than did the naturalsubstrates and reference substances.

[0048] The invention will be illustrated in greater detail by thefollowing examples.

EXAMPLE 1 E-17-Chloromethylene-4-aza-5α-androstan-3-one

[0049] To a solution of 3.1 mmol (1.0 g) ofE-17-chloromethylene-4-aza-androst-5-en-3-one in 140 mL ofdimethylformamide were added with stirring 59 mL of formic acid (85%)and 115.8 mmol (16 g) of potassium carbonate, and the reaction mixturewas heated at reflux for 8 hours. Toluene was then added to the reactionsolution, and the mixture was evaporated under vacuum. The residue wastaken up in water, and the resulting mixture was extracted withmethylene chloride. The combined extracts were treated with saturatedsodium carbonate solution, washed neutral with water, dried over sodiumsulfate and evaporated. The resulting crude product was crystallizedfrom acetone/n-hexane, which gave 543 mg of solid product (54%).

[0050] M.p.=148-151° C.; [α]_(D) ²⁰=+16° (CHCl₃).

EXAMPLE 2 E-17-Chloromethylene-4-methyl-4-aza-5α-androstan-3-one

[0051] To a suspension of 1.06 mmol (340 mg) ofE-17-chloromethylene-4-aza-5α-androstan-3-one in 9 mL ofdimethylformamide were added at room temperature and under an argonatmosphere 3.08 mmol (123 mg) of sodium hydride (60% in oil). Thereaction mixture was stirred 30 mm, and to it was then added dropwise asolution of 5.3 mmol (0.33 mL) of methyl iodide in 3.0 mL ofdimethylformamide. After about 60 minutes, 2 mL of methanol was addedfollowed after another 10 mm by 9 mL of saturated aqueous ammoniumchloride solution. The reaction mixture was diluted with water andextracted with toluene. The combined extracts were washed with water,dried over sodium sulfate and evaporated. The resulting crude productwas crystallized from acetone/n-hexane, which gave 154 mg of solidproduct (43%).

[0052] M.p.=150-162° C.; [α]_(D) ²⁰=−7° (CHCl₃).

EXAMPLE 3 E-17-Chloromethylene-4-aza-5α-androst-1-en-3-one

[0053] 1.34 mmol (430 mg) ofE-17-chloromethylene-4-aza-5α-androstan-3-one was suspended in 9 mL ofdioxane at room temperature and under an argon atmosphere and to thesuspension were then added 1.5 mmol (340 mg) of 2,3-dichloro-5,6-dicyano-p-benzo-quinone and 6.4 mmol (1.7 mL) ofbis-7-trimethylsilyl)trifluoroacetamide. The mixture was stirred first 3hours at room temperature and then 3 hours in an oil bath at about100-110° C. The reaction solution was diluted with methylene chlorideand then washed first with 2% aqueous sodium hydrogen sulfite solution,then with 2N hydrochloric acid and finally with water. The remainingextract was dried over sodium sulfate and evaporated. Crystallizationfrom acetone gave 243 mg of solid product (57%).

[0054] M.p.=275-282° C.; [α]_(D) ²⁰=−41° (CHCl₃).

EXAMPLE 4 E-17-Chloromethylene-4-methyl-4-aza-5α-androst-1-en-3-one

[0055] To a suspension of 0.87 mmol (279 mg) ofE-17-chloromethylene-4-aza-5α-androst-1-en-3-one in 7 mL ofdimethylformamide were added at room temperature and under an argonatmosphere 2.4 mmol (98 mg) of sodium hydride (60% in oil). The reactionmixture was stirred for 30 minutes, after which a solution of 7.5 mmol(0.47 mL) of methyl iodide in 3 mL of dimethylformamide was addeddropwise. After about 60 minutes, 2 mL of methanol was added followedafter an additional 10 mm by 9 mL of saturated aqueous ammonium chloridesolution. The reaction mixture was diluted with water and extracted withtoluene, and the extract was washed with water, dried over sodiumsulfate and evaporated. The resulting crude product was crystallizedfrom ethyl acetate, which gave 122 mg of solid product (42%).

[0056] M.p.=160-165° C.; [α]_(D) ²⁰=−47° (CHCl₃).

EXAMPLE 5 E-17-Chloromethylene-4-aza-5α-estran-3-one

[0057] To a suspension of 3.27 mmol (1 g) ofE-17-chloromethylene-4-aza-estr-5-en-3-one in 150 mL ofdimethylformamide were added with stirring 73.3 mL of formic acid (85%)and 121.55 mmol (16.8 g) of potassium carbonate, and the reactionmixture was heated at reflux for 12 hours. Toluene was then added to thereaction solution, and the mixture was evaporated under vacuum. Theresidue was taken up in water and extracted with methylene chloride. Thecombined extracts were treated with saturated sodium carbonate solution,washed neutral with water, dried over sodium sulfate and evaporated. Theresulting crude product was crystallized from acetone/n-hexane, whichgave 461 mg of solid product (46%).

[0058] M.p.=(178-200) 262-282° C.; [α]_(D) ²⁰=−21° (CHCl₃).

EXAMPLE 6 E-17-Chloromethylene-4-methyl-4-aza-5α-estran-3-one

[0059] To a suspension of 0.65 mmol (200 mg) ofE-17-chloromethylene-4-aza-5α-estran-3-one in 5.8 mL ofdimethylformamide were added at room temperature and under an argonatmosphere 1.7 mmol (73 mg) of sodium hydride (60% in oil). The reactionmixture was stirred 30 mm after which a solution of 3.2 mmol (0.2 mL) ofmethyl iodide in 2 mL of dimethylformamide was added dropwise. Afterabout 60 minutes, 1 mL of methanol was added followed after anadditional 10 mm by 4 mL of saturated aqueous ammonium chloridesolution. The reaction mixture was diluted with water and extracted withmethylene chloride. The combined extracts were washed with water, driedover sodium sulfate and evaporated. The resulting crude product waspurified by chromatography on Silica Gel 60 (eluent; methylenechloride/acetone 8/2). Crystallization from ethyl acetate then gave 131mg of solid product (62%).

[0060] M.p.=161-171° C.; [α]_(D) ²⁰=−88° (CHCl₃).

EXAMPLE 7 E-17-Chloromethylene-4-aza-5α-estr-1-en-3-one

[0061] 1 mmol (310 mg) of E-17-chloromethylene-4-aza-5α-estran-3-one wassuspended in 6.3 mL of dioxane at room temperature and under an argonatmosphere. Thereafter, 2.3 mmol (522 mg) of 2,3-dichloro-5,6-dicyano-p-benzoquinone and 9.8 mmol (2.6 mL) ofbis-(trimethylsilyl)trifluoroacetamide were added. The mixture wasstirred first 3 hours at room temperature and then 15 hours in an oilbath at 100-110° C. The reaction solution was diluted with methylenechloride and then washed first with 2% aqueous sodium hydrogen sulfitesolution, then with 2N hydrochloric acid and finally with water. Theremaining residue was dried over sodium sulfate and evaporated.Purification by chromatography on Silica Gel 60 (eluent: methylenechloride/methanol 98/2) gave 57 mg of solid product (18.5%).

[0062] [α]_(D) ²⁰=37° (CHCl₃).

1-6. (canceled).
 7. A 17-methylene-4-azasteroid compound of formula I:

wherein R²⁰ and R^(20a), independently of each other, each denote afluoro, chloro, bromo, azido, cyano, isocyano, rhodano, isothiocyano, aC₁-C₄-alkyl or a hydroxy-C₁-C₄-alkyl group, R¹⁰ denotes a hydrogen atomor a methyl group, R⁴ is selected from the group consisting of hydrogenand C₁-C₄-alkyl groups, and R¹ and R² each denote a hydrogen atom ortogether denote an additional bond.
 8. The 17-methylene-4-azasteroidcompound as defined in claim 7, wherein R⁴=H or Me and wherein R²⁰ andR^(20a), independently of each other, each denote F, Cl, Br or CN. 9.The 17-methylene-4-azasteroid compound as defined in claim 7, selectedfrom the group consisting of E-17-chloromethylene-4-aza-5α-estran-3-one,E-17-chloromethylene-4-aza-5α-androstan-3-one,E-17-chloromethylene-4-methyl-4-aza-5α-estran-3-one,E-17-chloromethylene-4-methyl-4-aza-5α-androstan-3-one,E-17-chloromethylene-4-aza-5α-estr-1-en-3-one,E-17-chloromethylene-4-aza-5α-androst-1-en-3-one,E-17-chloromethylene-4-methyl-4-aza-5α-androst-1-en-3-one,E-17-bromomethylene-4-methyl-4-aza-5α-estran-3-one,E-17-cyanomethylene-4-methyl-4-aza-5α-estran-3-one,Z-17-(1′)-chloroethylidene-4-methyl-4-aza-5α-androstan-3-one,Z-17-(1′)-chloroethylidene-4-methyl-4-aza-5α-estran-3-one,Z-17-(1′)-bromoethylidene-4-methyl-4-aza-5α-androstan-3-one andZ-17-(1′)-bromoethylidene-4-methyl-4-aza-5α-estran-3-one.
 10. A processfor making a 17-methylene-4-azasteroid compound of formula I:

wherein R²⁰ and R^(20a), independently of each other, each denote afluoro, chloro, bromo, azido, cyano, isocyano, rhodano, isothiocyano, aC₁-C₄-alkyl or a hydroxy-C₁-C₄-alkyl group, R¹⁰ denotes a hydrogen atomor a methyl group, R⁴ is selected from the group consisting of hydrogenand C₁-C₄-alkyl groups, and R¹ and R² each denote a hydrogen atom ortogether denote an additional bond; said process comprising the stepsof: a) reacting a 17-methylene steroid of formula II:

wherein R¹⁰ denotes a hydrogen atom or a methyl group, and R²⁰ denotes afluoro, a chloro, a bromo or a cyano group, with NalO₄ under catalyticmediation of KMnO₄ in a protic solvent to form a 3, 5-seco keto acid; b)cyclizing said keto acid with NH₄OAC in glacial acetic acid to form anunsaturated lactam and then reducing said unsaturated lactam with HCOOHin DMF to a saturated lactam of formula III:

wherein R¹⁰ and R²⁰ have the same meaning as in formula II, c) reactingthe saturated lactam of formula III with MeI and NaH to form the4-methyl-substituted compound of formula IV:

wherein R¹⁰ and R²⁰ have the same meaning as in formula II, or reactingthe saturated lactam of formula III by silyl-mediated oxidation to forma dehydrogenated compound of formula V:

wherein R¹⁰ and R²⁰ have the same meaning as in formula II; and d)reacting the dehydrogenated compound of formula V with MeI and NaH toform a 4-methyl-substituted compound of formula VI:

wherein R¹⁰ and R²⁰ have the same meaning as in formula II.
 11. Aprocess for making a 17-methylene-4-azasteroid compound of formula I:

wherein R²⁰ and R^(20a), independently of each other, each denote afluoro, chloro, bromo, azido, cyano, isocyano, rhodano, isothiocyano, aC₁-C₄-alkyl or a hydroxy-C₁-C₄-alkyl group, R¹⁰ denotes a hydrogen atomor a methyl group, R⁴ is selected from the group consisting of hydrogenand C₁-C₄-alkyl groups, and R¹ and R² each denote a hydrogen atom ortogether denote an additional bond; said process comprising the stepsof: a) reacting a 17-methylene steroid of formula VII:

wherein R¹⁰ denotes a hydrogen atom or a methyl group, and R^(20a)denotes a fluoro, a chloro, a bromo or a cyano group, with NalO₄ undercatalytic mediation of KmnO₄ in a protic solvent to form a 3, 5-secoketo acid; b) cyclizing said keto acid with NH₄OAc in glacial aceticacid to form an unsaturated lactam and then reducing said unsaturatedlactam with HCOOH in DMF to a saturated lactam of formula VIII:

wherein R¹⁰ and R^(20a) have the same meaning as in formula VII, c)reacting the saturated lactam of formula VIII with MeI and NaH to formthe 4-methyl-substituted compound of formula IX:

wherein R¹⁰ and R^(20a) have the same meaning as in formula VII, orreacting the saturated lactam of formula VIII by silyl-mediatedoxidation to form a dehydrogenated compound of formula X:

wherein R¹⁰ and R^(20a) have the same meaning as in formula VII; and d)reacting the dehydrogenated compound of formula X with MeI and NaH toform a 4-methyl-substituted compound of formula XI:

wherein R¹⁰ and R^(20a) have the same meaning as in formula VII.
 12. Apharmaceutical composition comprising a 17-methylene-4-azasteroidcompound of formula I:

wherein R²⁰ and R^(20a), independently of each other, each denote afluoro, chloro, bromo, azido, cyano, isocyano, rhodano, isothiocyano, aC₁-C₄-alkyl or a hydroxy-C₁-C₄-alkyl group; R¹⁰ denotes a hydrogen atomor a methyl group; R⁴ is selected from the group consisting of hydrogenand C₁-C₄-alkyl groups; and R¹ and R² each denote a hydrogen atom ortogether denote an additional bond; and at least one pharmaceuticallycompatible auxiliary agent and/or at least one pharmaceuticallycompatible carrier.
 13. The pharmaceutical composition as defined inclaim 12, wherein said 17-methylene-4-azasteroid compound is selectedfrom the group consisting of E-17-chloromethylene-4-aza-5α-estran-3-one,E-17-chloromethylene-4-aza-5α-androstan-3-one,E-17-chloromethylene-4-methyl-4-aza-5α-estran-3-one,E-17-chloromethylene-4-methyl-4-aza-5α-androstan-3-one,E-17-chloromethylene-4-aza-5α-estr-1-en-3-one,E-17-chloromethylene-4-aza-5α-androst-1-en-3-one,E-17-chloromethylene-4-methyl-4-aza-5α-androst-1-en-3-one,E-17-bromomethylene-4-methyl-4-aza-5α-estran-3-one,E-17-cyanomethylene-4-methyl-4-aza-5α-estran-3-one,Z-17-(1′)-chloroethylidene-4-methyl-4-aza-5α-androstan-3-one,Z-17-(1′)-chloroethylidene-4-methyl-4-aza-5α-estran-3-one,Z-17-(1′)-bromoethylidene-4-methyl-4-aza-5α-androstan-3-one andZ-17-(1′)-bromoethylidene-4-methyl-4-aza-5α-estran-3-one.
 14. A methodof treating a disease or condition due to an elevated level of anandrogen in an individual, said method comprising the step ofadministering an effective amount of at least one17-methylene-4-azasteroid compound of formula I:

wherein R²⁰ and R^(20a), independently of each other, each denote afluoro, chloro, bromo, azido, cyano, isocyano, rhodano, isothiocyano, aC₁-C₄-alkyl or a hydroxy-C₁-C₄-alkyl group, R¹⁰ denotes a hydrogen atomor a methyl group, R⁴ is selected from the group consisting of hydrogenand C₁-C₄-alkyl groups, and R¹ and R² each denote a hydrogen atom ortogether denote an additional bond; to said individual; wherein saideffective amount is an amount effective in reducing said elevated levelof said androgen in said individual.
 15. The method as defined in claim14, wherein said androgen is testosterone.
 16. The method as defined inclaim 14, wherein said at least one 17-methylene-4-azasteroid compoundis selected from the group consisting ofE-17-chloromethylene-4-aza-5α-estran-3-one,E-17-chloromethylene-4-aza-5α-androstan-3-one,E-17-chloromethylene-4-methyl-4-aza-5α-estran-3-one,E-17-chloromethylene-4-methyl-4-aza-5α-androstan-3-one,E-17-chloromethylene-4-aza-5α-estr-1-en-3-one,E-17-chloromethylene-4-aza-5α-androst-1-en-3-one,E-17-chloromethylene-4-methyl-4-aza-5α-androst-1-en-3-one,E-17-bromomethylene-4-methyl-4-aza-5α-estran-3-one,E-17-cyanomethylene-4-methyl-4-aza-5α-estran-3-one,Z-17-(1′)-chloroethylidene-4-methyl-4-aza-5α-androstan-3-one,Z-17-(1′)-chloroethylidene-4-methyl-4-aza-5α-estran-3-one,Z-17-(1′)-bromoethylidene-4-methyl-4-aza-5α-androstan-3-one andZ-17-(1′)-bromoethylidene-4-methyl-4-aza-5α-estran-3-one.
 17. A methodof reducing excessive amounts of an androgen present in an individual,said method comprising the step of administering an effective amount ofat least one 17-methylene-4-azasteroid compound of formula I:

wherein R²⁰ and R^(20a), independently of each other, each denote afluoro, chloro, bromo, azido, cyano, isocyano, rhodano, isothiocyano, aC₁-C₄-alkyl or a hydroxy-C₁-C₄-alkyl group, R¹⁰ denotes a hydrogen atomor a methyl group, R⁴ is selected from the group consisting of hydrogenand C₁-C₄-alkyl groups, and R¹ and R² each denote a hydrogen atom ortogether denote an additional bond; to said individual; wherein saideffective amount is an amount effective in reducing said excessiveamount of said androgen in said individual.
 18. A method of treatingacne, said method comprising the step of administering an effectiveamount of at least one 17-methylene-4-azasteroid compound of formula I:

wherein R²⁰ and R^(20a), independently of each other, each denote afluoro, chloro, bromo, azido, cyano, isocyano, rhodano, isothiocyano, aC₁-C₄-alkyl or a hydroxy-C₁-C₄-alkyl group, R¹⁰ denotes a hydrogen atomor a methyl group, R⁴ is selected from the group consisting of hydrogenand C₁-C₄-alkyl groups, and R¹ and R² each denote a hydrogen atom ortogether denote an additional bond; to an individual suffering from saidacne.